Incorporated by reference herein in its entirety is the Sequence Listing submitted on Nov. 17, 2009, entitled “sequence listing 11.13.2009.txt”, size of 2 kilobytes, created Nov. 13, 2009.
Parkinson's disease (PD) is a severely debilitating movement disorder resulting from progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta of the midbrain. Unfortunately, pharmacologic treatment for PD has not progressed beyond the use of dopamine mimetics, such as L-dopa, that only transiently alleviate motor symptoms. Furthermore, chronic use of L-dopa is associated with its own array of resultant pathologies such as dyskinesia (Lang and Lozano, 1998), cardiac arrhythmia and ischemic injury, and cerebral vascular dysfunction (Ben-Shlomo and Marmot, 1995). Ultimately, individuals suffering from PD will progress to the end stage of the disease, which is characterized by significant gait abnormalities and frequent falls, as well as a deficit in non-motor functions resulting in dementia, psychosis, and other autonomic disturbances (Djaldetti et al., 2004).
Over 1.5 million individuals are currently diagnosed with PD, with an additional 50,000 expected diagnoses annually, making this disease the second most prevalent neurological disorder behind Alzheimer's disease (Teismann and Schulz, 2004). While the reason for selective neuronal loss in PD remains poorly explained, chronic inflammation and activation of glial cells has been consistently observed in PD models as well as following postmortem evaluation, and provide a realistic target for slowing the progression of neuronal injury.
Currently, a precise etiology explaining PD remains to be discovered but recent research has revealed features of the disease that represent realistic targets for neuroprotective chemotherapeutic intervention that could mitigate the progressive loss of dopaminergic neurons. Among these observations are the presence of chronic inflammation and sustained expression of inducible nitric oxide (NOS2), accompanied by activation of the surrounding astrocytes and microglia.
Astrocytes have diverse and critical functions in the CNS that include providing energetic, antioxidant, and other trophic support essential for the survival and function of neurons. However, many neurological disease states, including PD, Alzheimer's disease, and ischemic injury are typically accompanied by varying degrees of astrocyte activation, or astrogliosis. While the exact cause of astrogliosis in PD is unknown, several reports have suggested that the activation of astrocytes is due to secretion of inflammatory cytokines, such TNF-α and IFN-γ, by the surrounding microglial cells. While some degree of activation is likely beneficial, reactive astrogliosis results in neuronal injury.
Astrogliosis results in increased production of various neurotoxic inflammatory mediators, including nitric oxide (NO), which contributes to progressive loss of nigro-striatal neurons. Supporting a deleterious role for excessive NO production in PD are postmortem observations of increased NOS2 expression in patients diagnosed with PD, as well as reports that deletion of the Nos2 gene in mice confers protection against MPTP-mediated neurotoxicity. Expression of NOS2 in diverse cell types is highly dependent upon the NF-κB signaling pathway and we previously demonstrated a requirement for NF-κB in the expression of NOS2 in activated astrocytes following stimulation with inflammatory cytokines and manganese. Multiple signaling pathways activate NF-κB through the IκB kinase (IKK) complex, leading to phosphorylation and degradation of the inhibitory IκB subunit and nuclear translocation of the transcriptionally active p65 subunit. Ensuing induction of Nos2 then typically requires binding of p65 to enhancer sequences on the Nos2 promoter and removal of constitutively bound nuclear co-repressor proteins such as NCoR2 by the nuclear proteosome.
Suppressing neuroinflammation has emerged as a potential strategy for treating disorders such as PD. Specifically, modulation of nuclear orphan receptors has been examined as a possible approach for suppressing inflammatory gene expression in astrocytes using traditional thiazoladinedione (TZD) ligands of PPAR-γ. The TZD ligand rosaglitazone (5-((4-(2-(methyl-2-pyridinylamino)ethoxy)phenyl)methyl)-2,4-thiazolidinedione) appears to antagonize NF-κB by stabilizing NCoR2 at the proximal p65 enhancer element in RAW macrophages. However, another drug in this series, pioglitazone, confers only partial neuroprotection in the MPTP model of Parkinson's disease, preserving dopaminergic cell bodies in the substantia nigra but not dopaminergic fibers in the striatum. However, there remains a pressing need for better compounds and strategies to treat neurodegenerative conditions that have a neuroinflammatory component in their progression, including Parkinson's disease.
U.S. Pat. No. 5,948,808 discloses use of indole-3-carbinol, diindolylmethane and substituted analogs as antiestrogenic compounds suitable for treating estrogen-dependent tumors. U.S. Pat. No. 7,232,843 discloses diindolylmethane, ring substituted diindolylmethane, and C-substituted diindolylmethanes and analogs thereof as antiestrogenic and antitumoric agents. The disclosures of these U.S. patents are specifically incorporated by reference herein.
The present invention is directed toward overcoming one or more of the problems discussed above.